The Shaker-type K+ (Kv1) channels are heterotetramers composed of α1.2 and α1.5, which mediate vasodilation of cerebral circulation. This thesis project pursued three hypotheses to define several key processes that influence Kv1 channel function and expression levels in cerebrovascular smooth muscle cells (cVSMCs) of rat.
We first hypothesized that the ancillary Kvβ2 subunits that complex with α1 pore-forming subunits, promote the basal expression of functional Kv1 channels in the cVSMCs of rat. In support of the hypothesis, lowering the expression of Kvβ2 subunits using Kvβ2—specific morpholino antisense concomitantly reduced the expression of α1.2 subunits in cerebral arteries, and also reduced the contribution of Kv1 channels to the resting membrane potential and resting diameter of isolated, pressurized cerebral arteries. Second, we hypothesized that a down-regulation of functional Kv1 channels contributes to the elevated cerebrovascular tone of hypertensive rats and that this event is associated with a loss of ancillary Kvβ2 subunits. Using spontaneously hypertensive rat (SHR) and aortic-banded (Ao-B) rat models, we report that a loss of Kv1 channel dilator function and expression as a result of transcriptional down-regulation of pore-forming α subunit(s) contribute to the elevated cerebrovascular tone in hypertensive rats. Further, the deficiency of Kv1 channels was associated with a post-transcriptional down-regulation of Kvβ2 subunits.
Subsequent studies demonstrated for the first time that PSD 95 ( Post Synaptic Density 95), a well characterized molecular scaffold in neurons is expressed at the surface of cVSMCs and complexes with α1.2 pore-forming subunits in rat cerebral arteries. Further, we hypothesized that the Kv1 channels mediate the expression of PSD 95 in rat cerebral arteries and that the loss of Kv1 channels in cerebral arteries of hypertensive rats is associated with a down-regulation of the PSD 95 scaffolds. In support of the hypothesis, the knockdown of α1 subunits using specific siRNAs concomitantly reduced PSD 95 expression in rat cerebral arteries. Furthermore, a post-transcriptional loss of PSD 95 was observed in cerebral arteries of SHR and Ao-B rats.
Collectively, this thesis provide evidence for a dynamic interplay between Kv1 channels, ancillary Kvβ2 subunits and PSD 95 scaffolds in rat cerebral arteries.
|Advisor:||Rusch, Nancy J.|
|School:||University of Arkansas for Medical Sciences|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 70/08, Dissertation Abstracts International|
|Subjects:||Toxicology, Surgery, Pharmacology, Physiology|
|Keywords:||Cerebral arteries, Hypertension, MAGUK, Potassium channels, Vascular smooth muscle|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be